Friday, May 16, 2025
5/16/2025
Molecular mechanisms of Candida albicans gut colonization - Project Summary Candida albicans is a eukaryotic component of mammalian gut microbiota, where it exists in a commensal state, both benefitting from and acting upon the host environment without causing symptoms. C. albicans is also the most common cause of fungal infectious disease, which occurs upon overgrowth and escape to ectopic sites. Existing research on commensalism has largely ignored eukaryotes and is devoid of mechanistic detail. It is unknown how pathobiont commensals establish their niches, or what determines the transition from commensal growth to pathogenesis. As such, tools for the timely diagnosis and treatment of serious fungal infections are lacking. Our laboratory has taken unbiased genetic and hypothesis-directed approaches to identify fungal regulators of gut colonization. Using a library of >700 barcoded homozygous null mutants that we created, we identified 14 fungal transcription factors (TFs) that determine C. albicans fitness in a mouse model of gut colonization. We hypothesize that complex signals in local gut niches lead to TF activation, and activated TFs modulate the expression of the fungal effectors that directly foster commensalism. Recently, we implemented a C. albicans -Seq (CCS), which uses transposase-transcription factor fusion proteins to permanently mark genomic sites of transcription factor binding by transposon integration. Pairing CCS with transcriptomic analysis of mutants affecting three TFs (Efg1, Wor1, and Czf1), we captured the in-host activity of these regulators during active gut colonization. We then mined these datasets to predict and validate the first two commensal effector proteins to be described in this species, determining that the GPI-anchored cell wall chitinase Cht2 promotes commensal fitness, and that the secreted aspartyl protease Sap6 inhibits commensal fitness. - C. albicans commensal effectors; and (2) use host transcriptional responses to WT and mutant C. albicans lacking specific effector genes to capture the impact of fungal colonization on specific host cell types and to generate testable hypotheses for effector function.
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